Oxidative stress and inflammation have been proposed to play key roles in aging and neurodegenerative diseases associated with aging such Alzheimer's disease and Parkinson's disease. Thus, an understanding of the mechanisms in the brain that leads to an increase in inflammation and oxidative stress could lead to rational therapeutic interventions in aging and neurodegenerative diseases. We have been examining nutritional interventions such as spinach or blueberries, which lead to improvements in learning and memory in aged rats and modulation of many biomarkers of brain aging. In the past granting period, we have demonstrated that inflammation and oxidative stress occur in the aged brain and that these processes may contribute to the declines in cognitive function. We have demonstrated that both natural and pharmaceutical antioxidant and anti-inflammatory agents are capable of improving cognitive deficits in aged rats and this is concomitant with changes in neuronal signal transduction. We will examine potential mechanisms by which these diets alter brain aging. One potential mechanism is an amelioration of an increase in inflammation with age. Microglial cells are an important source of reactive oxygen species (ROS) in the brain as well as other inflammatory signals such as proinflammatory cytokines and therefore may play a central role in modulating CNS oxidative stress and neurodegenerative diseases. We plan to investigate immune function in the progression of neurodegeneration in the aged brain and the potential for therapeutic intervention in neurodegenerative diseases such as Alzheimer's disease. We hypothesize that oxidative stress and inflammation are primary drivers of neuronal dysfunction in the aged brain;furthermore, age-related changes in microglia are the critical primary events in brain aging and neurodegenerative disease. Specifically, in the cerebellum, microglial production of tumor necrosis factor (TNF)alpha leads to further inflammation and oxidative stress. Therapeutic interventions that reduce TNFalpha and/or microglial activation will improve neuronal function and concomitantly learning and memory in aged animals will be improved.